Epilepsy with migrating focal seizures

Abstract

ObjectiveTo report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine.MethodsWe reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and KCNT1 mutations, in collaboration with the network of the French reference center for rare epilepsies.ResultsThe mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified KCNT1 variants clustered as “hot spots” on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency.ConclusionsThe majority of the KCNT1 mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients.

In silico model reveals the key role of GABA in KCNT1‐epilepsy in infancy with migrating focal seizures

“…These encompass an increase of excitability due to an increase of AP repolarization rate, a disinhibition due to a higher impact on inhibitory interneurons, an aberrant connectivity of neural networks linked to the impact of seizure in brain maturation, and molecular interactions in the C‐terminal part of the channels 8 . The distribution of the variants outside the C‐terminal region argues against the last hypothesis 3,16 . Our study identified a differential effect of the GOF of slack, with a stronger impact on GABAergic interneurons as compared to pyramidal neurons, which is in line with the disinhibition hypothesis 8,17 .…”

“…8 The distribution of the variants outside the C-terminal region argues against the last hypothesis. 3,16 Our study identified a differential effect of the GOF of slack, with a stronger impact on GABAergic interneurons as compared to pyramidal neurons, which is in line with the disinhibition hypothesis. 8,17 Although pyramidal neurons are also affected, the impact on interneurons was higher regarding the maximum of the firing rate.…”

“…1,2 In 1995, this syndrome was identified based on its main features, 1 which we refined in 2019. 3,4 EIMFS is characterized by a seizure onset before the age of 6 months in a previously healthy child, followed by a stormy phase of seizures with a specific and pathognomonic ictal electroencephalographic (EEG) pattern called "migrating" seizure with drug resistance and a psychomotor regression resulting in a developmental global delay with an acquired microcephaly. We described two EEG markers of the EIMFS ictal pattern, namely, the time delay index and the phase coherence index, which were specific to EIMFS with KCNT1 pathogenic variants.…”

“…Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare developmental and epileptic encephalopathy (DEE) that affects approximately .11 children per 100 000 births per year 1,2 . In 1995, this syndrome was identified based on its main features, 1 which we refined in 2019 3,4 . EIMFS is characterized by a seizure onset before the age of 6 months in a previously healthy child, followed by a stormy phase of seizures with a specific and pathognomonic ictal electroencephalographic (EEG) pattern called “migrating” seizure with drug resistance and a psychomotor regression resulting in a developmental global delay with an acquired microcephaly.…”

Cardiac phenotypic spectrum ofKCNT1mutations

“…An additional patient with the same mutation and multi-drug refractory seizures has also been reported. 4,11,12 This patient was diagnosed at 12 years of age and has had a normal 24-hour Holter evaluation and has done well from a cardiac standpoint. An unspecified cardiac arrhythmia has been reported in a young patient with familial KCNT1 c.2782 C > T; p. Arg928Cys mutation.…”